Throughout this application, various publications are referenced by author and date within the text. Full citations for these publications may be found listed alphabetically at the end of the specification immediately preceding the claims. All patents, patent applications and publications cited herein, whether supra or infra, are hereby incorporated by reference in their entirety. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein.
Abnormalities in differentiation are common occurrences in human cancers ((1) Fisher and Grant, 1985; (2) Waxman, 1995). Moreover, as cancer cells evolve, ultimately developing new phenotypes or acquiring a further elaboration of preexisting transformation-related properties, the degree of expression of differentiation-associated traits often undergo a further decline. These observations have been exploited as a novel means of cancer therapy in which tumor cells are treated with agents that induce differentiation and a loss of cancerous properties, a strategy called ‘differentiation therapy’ ((2–4) Waxman et al., 1988, 1991; Jiang et al., 1994; Waxman, 1995). In principle, differentiation therapy may prove less toxic than currently employed chemotherapeutic approaches, including radiation and treatment with toxic chemicals. The ability to develop rational schemes for applying differentiation therapy clinically require appropriate in vitro and in vivo model systems for identifying and characterizing the appropriate agent or agents that can modulate differentiation in cancer cells without causing undue toxicity to normal cells.